This proposal integrates liquid chromatography, mass spectrometry based metabolite profiling with well- characterized patient cohorts to identify and characterize novel cardiovascular risk markers in end-stage renal disease (ESRD). This project directly engages two NIDDK research programs: 1) Functional Metabolomics, which applies metabolomics towards "discovering new, potentially mechanistic relationships between changes in metabolite profile and the etiology or pathology of specific metabolic diseases or syndromes";and 2) End- Stage Renal Disease, which "supports investigation on the pathogenesis of the uremic state, [and] on end- stage renal disease treatment by peritoneal and hemodialysis". Candidate: Eugene Rhee received his MD and MA Bioethics from the University of Pennsylvania, and completed Internal Medicine residency and chief residency at the Massachusetts General Hospital (MGH) and Nephrology fellowship in the combined MGH/ Brigham &Women's program;he is currently on faculty in the MGH Nephrology Division. He is pursuing training in a laboratory dedicated to understanding the vascular complications of metabolic disease, with access to a unique metabolite profiling resource at the Broad Institute. The applicant's long-term goal is to become an R01 funded investigator with expertise in uremia. Environment: Dr. Rhee's mentors provide complementary expertise. Dr. Robert Gerszten is a co-PI of the Metabolite Profiling Platform at the Broad, and Director of Translational Research at the MGH Heart Center. Dr. Ravi Thadhani is Director of Clinical Research in the MGH Nephrology Division, with a strong background in ESRD research. Both investigators have a robust track record of mentorship. The applicant's career development plan entails rigorous training in metabolite profiling, direct experience and coursework in clinical research, and close guidance from a diverse and dedicated network of scientific advisors. Research: This proposal builds on preliminary experiments that highlight alterations in select metabolic pathways in ESRD, and specifically advances 3 candidate metabolites - adipic acid, kynurenic acid, and choline - with potential relevance to cardiovascular outcomes. In Aim 1, metabolite profiling will be performed on plasma from patients enrolled in a longitudinal ESRD cohort study (ArMORR - Accelerated Mortality on Renal Replacement). Using a nested case-control design, metabolite profiles from individuals who die within one year of cardiovascular causes will be compared with metabolite profiles from individuals who survive at least one year. In Aim 2, the relationship between hemodialysis intensity and metabolite profiles in these patients will be examined. In Aim 3, metabolite profiling will be performed on individuals with earlier stages of kidney disease to determine the relationship between kidney function and metabolite profiles. Ultimately, identifying novel cardiovascular risk markers in ESRD, understanding how they are affected by hemodialysis, and recognizing when they arise during disease progression could yield new metrics by which to assess ESRD and lead to new therapeutic approaches. PUBLIC HEALTH RELEVANCE: The risk of heart disease is significantly increased in individuals with kidney disease, particularly end-stage renal disease. The goal of this proposal is to identify new blood markers that predict cardiovascular death in patients with end-stage renal disease, and to provide new insights into why kidney disease increases the risk of heart disease.